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<p>The mycobacterial ABC transporter IrtAB features an ABC exporter fold, yet it imports iron-charged siderophores called mycobactins. Here, we present extensive cryo-EM analyses and DEER measurements, revealing that IrtAB alternates between an inward-facing and an outward-occluded conformation, but does not sample an outward-facing conformation. When IrtAB is locked in its outward-occluded conformation in nanodiscs, mycobactin is bound in the middle of the lipid bilayer at a membrane-facing crevice opening at the heterodimeric interface. Mutations introduced at the crevice abrogate mycobactin import and in corresponding structures, the crevice is collapsed. A conserved triple histidine motif coordinating a zinc ion is present below the mycobactin binding site. Substitution of these histidine residues with alanine results in a decoupled transporter, which hydrolyzes ATP, but lost its capacity to import mycobactins. Our data suggest that IrtAB imports mycobactin via a credit-card mechanism in a transport cycle that is coupled to the presence of zinc.</p>

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The mycobacterial ABC transporter IrtAB employs a membrane-facing crevice for siderophore-mediated iron uptake

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月29日

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  • Imre Gonda,
  • Simona Sorrentino,
  • Laura Galazzo,
  • Nicolas P. Lichti,
  • Fabian M. Arnold,
  • Ahmad R. Mehdipour,
  • Enrica Bordignon,
  • Markus A. Seeger

摘要

The mycobacterial ABC transporter IrtAB features an ABC exporter fold, yet it imports iron-charged siderophores called mycobactins. Here, we present extensive cryo-EM analyses and DEER measurements, revealing that IrtAB alternates between an inward-facing and an outward-occluded conformation, but does not sample an outward-facing conformation. When IrtAB is locked in its outward-occluded conformation in nanodiscs, mycobactin is bound in the middle of the lipid bilayer at a membrane-facing crevice opening at the heterodimeric interface. Mutations introduced at the crevice abrogate mycobactin import and in corresponding structures, the crevice is collapsed. A conserved triple histidine motif coordinating a zinc ion is present below the mycobactin binding site. Substitution of these histidine residues with alanine results in a decoupled transporter, which hydrolyzes ATP, but lost its capacity to import mycobactins. Our data suggest that IrtAB imports mycobactin via a credit-card mechanism in a transport cycle that is coupled to the presence of zinc.